A comprehensive program is proposed for continued study of the structure, function, and genetic variation of human plasma proteins. The program has three major components: 1) continued studies of a series of alpha- and beta- plasma glycoproteins; 2) analysis of the structural changes in genetic variants of human serum albumin and other plasma proteins; 3) study of the structure and function of the oligosaccharides of multiglycosylated plasma proteins. Most of the 100 or more plasma proteins are alpha- or beta- glycoproteins. Some have identified function and clinical significance, especially in complement action and blood coagulation, but for others, little is known about their structure or function. Emphasis will be on the determination of the amino acid sequence, disulfide bonding pattern, localization and kind of carbohydrate groups and the combining sites of ligands such as metal ions and heme. Correlation of function and structure will be sought and interrelationships with other plasma proteins will be investigated. Some correlations will be done in cooperation with other groups studying charges in plasma proteins in disease, genetic polymorphism and variation, metabolism and membrane uptake, and three-dimensional structure. Protein sequence analysis is being used to determine the structural chances in human serum albumin in more than 100 serum specimens containing albumin genetic variants obtained from collaborators and investigators throughout the world. Many specimens were collected in large population genetic surveys, including follow-up studies of the F1 children in Hiroshima and Nagasaki, Japan. To date, the site of amino acid substitution has been determined in more than 25 different named specimens. This work is providing important new information on the frequency of mutation of the human serum albumin gene and on the sites of mutation. The overall objective will be to identify broad principles that affect the structure, the function, and the evolution of groups of plasma proteins that comprise a number of interrelated and interacting systems and families of proteins. The goals are to make a major contribution to knowledge about human plasma proteins, to integrate information gained from in vitro study with in vivo significance of proteins from human blood plasma.